Erodible matrix for sustained release bioactive composition

ABSTRACT

A sustained release composition for releasing a biologically active compound into an aqueous liquid environment comprises said biologically active compound dispersed in a bioerodible matrix, the matrix comprising a mixture of 
     a. 5% to 99.5% by weight of a solid water-dispersible polyether diol having a molecular weight from about 1000 to about 20,000, and 
     b. 95 to 0.5% by weight of an erosion rate modifier which is an amphiphilic compound insoluble in the aqueous liquid. 
     Dosage forms comprising the erodible matrix are prepared by molding, particularly by injection molding.

REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part application of copendingapplication Ser. No. 633,604, filed July 23, 1984, now U.S. Pat. No.4,629,621.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to sustained release compositions for bioactivecompounds and more particularly to sustained release oral dosage formsincorporating a drug in an erodible matrix.

2. Description of the Prior Art

In chemotherapy of diseases it is frequently desirable to maintain theconcentration of the therapeutic drug at a relatively constant level inthe blood or organ being treated. One method for achieving this goal isto administer the drug continuously at a rate which balances its rate ofmetabolism and/or excretion. In a hospital environment this goal can beattained by intravenously administering a drug, but outside of such anenvironment this method of administration is impractical in the greatmajority of cases. Consequently, the most common method of administeringa drug is orally, in the form of tablets, capsules, and the like, whichpreferably have sustained release characteristics. The drug releasedtherefrom is usually absorbed from the gastrointestinal tract andreaches the target organ via the blood stream.

Among the various types of sustained release dosage forms which havebeen developed are erodible matrices, i.e., dosage forms wherein thedrug is entrapped in a matrix which upon ingestion gradually decomposesin the intestinal fluid thereby releasing the drug for absorption. Anexample of such a dosage form is found in Schmitt, U.S. Pat. No.4,346,709, wherein the device comprises a drug dispersed in abioerodible polymer which is a poly(orthoester) or apoly(orthocarbonate) containing an erosion rate modifier. The erosionrate modifiers of Schmitt are mono- and polybasic organic acids whichadjust the pH at the surface of the erodible matrix to accelerate orretard the decomposition of the polymer in the gastric or intestinalenvironment.

In a further example, Sothmann, et al., in U.S. Pat. No. 4,351,825,disclose a sustained release oral dosage form wherein a drug isdispersed in a matrix of a water-insoluble polymethacrylate, e.g., acopolymer of acrylic and methacrylic acid esters containing quaternaryammonium groups or a copolymer of methyacrylic acid and methylmethacrylate, which has an anionic character. The granules of the matrixmaterial are mixed with the active drug and an erosion rate modifierwhich is an ester of a long chain fatty acid with glycerine or a longchain alcohol.

Additionally, Kleber, et al., in U.S. Pat. No. 4,333,919, disclosecontrolled release formulations comprised of a drug mixed with acopolymer of lactic and glycolic acids. The formulations may alsocontain adjuvants such as glyceryl distearate. The formulations areprimarily intended for growth stimulants for ruminants. Accordingly,they are administered by filling open-ended steel cylinders with theformulations and placing the cylinders in the rumen of the animal. Thefilled steel cylinders remain in the rumen, and the growth stimulant isgradually released as the matrix is eroded by the rumen fluids.

It seems evident from these disclosures, and others, that the erodibleformulations of the prior art have generally required specially preparedpolymers, and that the rate of erosion of such polymers cannot always beadjusted to provide for preferential release of the drug in a particularportion of the gastrointestinal tract, e.g., in the stomach or smallintestine.

Therefore, a need has continued to exist for an erodible matrix,prepared from readily available materials which are suitable forsustained release pharmaceutical formulations, wherein the rate oferosion can be substantially controlled.

SUMMARY OF THE INVENTION

Accordingly, it is an object of this invention to provide an oral,sustained release dosage form.

A further object is to provide an oral, sustained release dosage formincorporating an erosion rate modifier substance.

A further object is to provide an oral, sustained release dosage formwhose formulaton and/or structure can be adjusted to release itsmedication either in the stomach or the small intestine.

A further object is to provide a sustained release compositioncontaining a bioactive compound which is released by erosion of thematrix in an aqueous liquid environment.

A further object is to provide a liquid-erodible composition wherein therate of erosion can be adjusted by incorporation of an erosion ratemodifier.

A further object is to provide a liquid-erodible composition wherein therate of erosion can be adjusted to vary with the pH of the surroundingaqueous liquid.

Additional objects will become apparent from the description of theinvention which follows.

The objects of the invention are achieved by a composition capable ofbeing eroded in an aqueous liquid environment comprising

(a) about 5% to about 99.5% by weight of a solid polyethylene glycolhaving a molecular weight from about 1000 to about 20,000, and

(b) about 95% to about 0.5% of an erosion rate modifier which is anamphiphilic compound insoluble in the aqueous liquid.

A sustained release dosage form according to the invention comprises amatrix of the erodible composition of the invention having dissolved ordispersed therein a bioactive compound to be released over a period oftime.

BRIEF DESCRIPTION OF THE DRAWING

The sole figure is a plot of the release rate of a drug from the dosageforms of the invention prepared in Example 9 (A-C).

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The property of the composition of this invention which makes it usefulin sustained release preparations of bioactive material is its erodiblecharacter. Because it is the surface of an erodible composition whichdissolves or decomposes into the surrounding medium and the erodingliquid does not substantially penetrate its structure, it is possible toachieve superior control of the dissolution rate of the solidcomposition, so that it may be used in a variety of applications.

The erodible matrix of this invention is especially suitable forincorporating a drug to be administered over a period of time via theintestinal absorption route. It is formed from a composition comprisingsolid water-dispersible polyether diol and an amphiphilic erosion ratemodifier, and the kinetics of its drug release are determined by theproperties of the matrix and the shape of the dosage form. Accordingly,the rate of release can be controlled by varying the size and shape ofthe dosage form as well as the proportion and type of the erosion ratemodifier.

One particular dosage regimen wherein the controlled release compositionof this invention is useful is in the administration of drugs which havea relatively short biological half-life in the body. Such drugs can beincorporated into a dosage form made from the erodible controlledrelease matrix of this invention which is designed to release the drugcontinuously over a period of 6 to 18 hours in order to provide acontinuous supply of the drug to the patient and thereby maintain atherapeutic level of the drug in the patient. Such relatively long-liveddosage forms will have an erodible matrix of the invention whichincorporates a relatively large amount of the release rate modifier,e.g., 60 % to 20 % by weight of the composition. Another dosage regienwhich can make use of the controlled release matrix of this invention isfound in the case of drugs which have a sufficient half-life, e.g., upto 18 hours, so that sustained release of the medication is notnecessary to maintain a therapeutic level in the patients plasma or thetarget organ. However, when long-lasting drugs of this type are given ina dosage form which releases the medication all at once, the initilconcentration of the drug in the patients bloodstream may exceed thetherapeutic range and result in undesirable side effects. With suchdrugs it is desirable to control the rate of absorption to avoid aninitial overdose, and release of the drug over a period of 30 minutes totwo hours is will accomplish this goal. For this relatively rapid, butcontrolled, release the amount of release rate modifier will be presentin amounts of about 10 % to about 0.5 % by weignt.

The polyethylene glycol component of the erodible matrix may be presentin amounts ranging from about 5 % to about 99.5 % by weight of theerodible matrix. When a relatively slow release composition is desired,the proportion of the polyethylene glycol component will range fromabout 40 % to about 80 % by weight, while when a relatively rapidcontrolled release is desired, the proportion of the polyethylene glycolcomponent will be from about 90 % to about 99.5 % by weight.

The erosion rate modifier is an insoluble amphiphile, that is, amaterial whose molecule possesses a hydrophilic portion and a lipophilicportion, usually located at opposite ends of a relatively elongatedmolecule. The presence of lipophilic portions in the erosion ratemodifier slows down the rate at which the matrix is eroded when incontact with an aqueous liquid environment. Therefore, the rate oferosion can be slightly retarded by incorporating relatively smallamounts of erosion rate modifier and greatly retarded by incorporatingrelatively large amounts of erosion rate modifier.

The erosion rate modifier can also be chosen to vary the rate of erosionunder varying conditions of pH. For example, if the erosion ratemodifier is a long chain fatty acid such as myristic acid, the erosionrate of the matrix will be relatively slow in acid media wherein thecarboxyl group of the myristic acid is not ionized and the amphiphilicmolecule is accordingly relatively hydrophobic. On the other hand, underbasic conditions the carboxyl group is ionized, and thereforehydrophilic, which makes the erosion rate considerably faster.Evidently, a dosage form made from such a formulation releasesrelatively little of a drug in the acidic environment of the stomach,but subsequently more freely releases the drug in the basic environmentof the small intestine. In the event that erosion of the matrix in thestomach is desired, then erosion rate modifiers having basic groupswhich are ionized under acidic conditions can be incorporated in thematrix composition.

The erosion rate modifier can also be chosen to compensate for theeffects of charged forms of the bioactive compound on the erosion rate.When the bioactive compound, e. g., a drug, is present in the matrix ofthe invention in amounts greater than about 2-3 % by weight of the totalcomposition, the ionic character of the drug can affect the rate oferosion at various pH's of the eroding environment. For, example if theerodible matrix contains a basic drug, which will assume a positivecharge in the acidic environment of the stomach, thereby increasing theerosion rate, an acidic erosion rate modifier, e. g., a long chain fattyacid such as myristic acid, may be used as an erosion rate modifier. Theacid will remain un-ionized in the acidic environment of the stomach andthereby act to retard the erosion rate and counterbalance the effect ofthe basic drug.

Use of erosion rate modifiers devoid of ionizable hydrophilic groups,such as long chain aliphatic alcohols, results in an erodible matrixwhose rate of erosion is not greatly affected by the pH of theenvironment.

The erosion rate modifier may be present in the erodible compositions ofthis invention in amounts of about 95 % to about 0.5 % by weight. When arelatively slow-release matrix is desired, the erosion rate modifierwill preferably constitute about 60 % to about 20 % by weight of thecomposition, while when a relatively rapid controlled release matrix isdesired, the erosion rate modifier will be present in a proportion ofabout 10 % to about 0.5 % by weight.

Suitable erosion rate modifiers include C₁₂ -C₂₀ fatty acids, such aslauric acid, myristic acid, palmitic acid, stearic acid, and arachidicacid; C₁₂ -C₂₀ alcohols, such as lauryl alcohol, myristyl alcohol,palmityl alcohol, stearyl alcohol and arachidyl alcohol, amphiphilicesters of fatty acids with glycerol, particularly monoesters of C₁₂ -C₂₀fatty acids such as glyceryl monopalmitate, C₁₂ -C₂₀ amines such aslauryl amine, myristyl amine, palmityl amine, stearyl amine andarachidyl amine, and amides of C₁₂ -C₂₀ fatty acids.

In various dosage forms embodiments of this invention, the rate of drugrelease can be controlled by varying the shape of the dosage form or bycoating the surface of the dosage form. For example, an erodible dosageform of the invention may have a cylindrical shape wherein the height ofthe cylinder is much greater than the diameter, so that most of the areaof the cylinder exposed to the erosive action of the aqueous liquidmedium is constituted by the curved peripheral surface of the cylinder.When such a cylinder is immersed in a liquid medium the peripheralsurface of the cylinder will be eroded. As the diameter of the cylinderdecreases through its erosion, the area of the peripheral surfaceexposed to the erosive action of the aqueous liquid environmentdecreases proportionally. Therefore, the dosage form will erode at arate which will provide approximately first order drug release kinetics.If a cylindrical dosage form has a relatively small height compared withits diameter, so that most of the exposed area is provided by the basesof the cylinder, the eroding surface area of the dosage form will notchange greatly as erosion proceeds. In this case the rate of drugrelease will be substantially constant, i. e., the drug release kineticswill be approximately zero order.

In another embodiment, the surface of the dosage form can be partiallycoated with a liquid-impervious coating so that only certain surfaces ofthe dosage form are exposed to the erosive action of the medium. Thismethod also allows for adjusting the kinetics of drug release. Forexample, if a cylindrical dosage form is coated on its curved peripheralsurface so that only the ends of the cylinder are exposed to the erosiveaction of the medium, the area of the dosage form exposed to erosiveaction will not change with time. In this embodiment, therefore, thedrug will be released at a constant rate, i. e., the release kineticswill be approximately zero order.

In order to assure that the rate of drug release will actually remainsubstantially constant for this coated cylindrical dosage form, it isnecessary that the coating be non-self-supporting. If the coating isself-supporting it will extend beyond the ends of the cylindricalportion remaining after a portion of the dosage form has been eroded.This extension will interfere with the access of the eroding aqueousliquid medium to the ends of the cylinder and will, accordingly, affectthe kinetics. Therefore, the preferred coating for this type of dosageform is a very thin friable material which is not self-supporting. Withsuch a coating, any portion extending beyond the end of the cylinderafter the immediately underlying matrix has been eroded will be brokenoff as the dosage form is subjected to agitation in the gastrointestinaltract, thus keeping the uncoated ends of the cylinder fully exposed tothe erosive action of the medium.

In most cases it will be convenient to apply the coating material in theform of a melt which solidifies by cooling on the surface of the dosageform. Preferred coating materials are long chain fatty acids having 12to 20 carbon atoms. Such acids include lauric acid, myristic acid,palmitic acid, stearic acid and arachidic acid. The thickness of thecoating will typically be from about 0.02 mm to about 0.5 mm.

Additional ingredients can be incorporated into the erodible compositionof this invention to modify and/or control the properties of thecomposition. For example, in order to improve the compatibility betweenthe polyethylene glycol and the erosion rate modifier and prevent phaseseparation when the molten composition is cooled, a modifiedpolyethylene glycol wherein the OH groups at one or both ends areesterified with long chain fatty acids may be added to the mixture.Suitable long chain fatty acids are aliphatic fatty acids having fromabout 12 to about 20 carbon atoms such as those disclosed above.Preferred polyethylene glycols to be used in preparing the esterifiedPEG compatibility enhancers are those having a molecular weight fromabout 200 to 10000, preferably from about 200 to about 2000. PEG 400 andPEG 600 are particularly preferred materials for preparing theesterified PEG's. For example, the esterified PEG's may be themonoesters and preferably the lauric or stearic ester. More preferredesters are the diesters, particularly the dilauroyl and distearoylesters. These modified polyethylene glycols are prepared by conventionalesterification procedures well known to those skilled in the art, suchas reacting the polyethylene glycol with the acid chloride of the chosenacid. The modified polyethylene glycol may be incorporated into thecompositions of this invention in any effective amounts, such as in anamount up to about 10 % by weight, preferably from about 0.1 % to about10 % by weight, and particularly about 2 % by weight.

Starch may also be added to the erodible mixture of this invention as adisintegrant in order to adjust the erosion rate. The starch tends toenhance the erodible characteristics of the composition by causing thesolid material to dissolve from the surface without penetration of theaqueous liquid into the interior of the solid form. Any type of starchmay be used, particularly a pharmaceutically acceptable and readilyavailable form of starch, such as cornstarch. Starch may be present inamounts of from about 5 % by weight to about 60 % by weight, preferablyfrom about 10 % by weight to about 50 % by weight, and more preferablyfrom about 20 % by weight to about 40 % by weight.

Molding adjuvants may also be added to the compositions of thisinvention. It has been found that the addition of a polyethylene oxide(PEO) having a molecular weight (MW) from about 100,000 to about 5×10⁶has beneficial effects on the viscosity and plasticity of thecomposition. This provides for easier mold filling and release of moldedforms from the molds, especially when molded dosage forms of thisinvention are prepared by injection molding. The PEO may be present inan effective amount up to about 2 % by weight, preferably from about0.05 % by weight to about 1 % by weight, and most preferably about 0.1 %by weight. It will be appreciated by those skilled in the art thatinjection molding of compositions containing a relatively large numberof ingredients, such as the compositions of this invention, is notcommon. Hence, some experimentation may be required to determine theexact amount of molding adjuvant needed for a given composition.

The erodible matrix of this invention is useful wherever controlledrelease of a material into an aqueous liquid environment is desired.Such an erodible material may be used, for example, without anincorporated drug as a coating for a substance designed for a delayeddissolution after immersion in an aqueous liquid. It may serve a similarfunction when employed as a plug for a container intended to release amaterial on a delayed-action basis when immersed or contacted with anaqueous liquid.

The erodible composition of this invention may also contain anecological agent dispersed therein in order to provide for gradualrelease of the ecological agent into an aqueous liquid environment. Anecological agent is defined for purposes of this invention as anon-pharmaceutical substance which has a biological effect on plants oranimals in the environment. An ecological agent may be a pesticide, suchas an insecticide or herbicide, a fertilizer, a pheromone, a plantgrowth hormone, or the like. When dosage forms made from compositionscontaining such bioactive ingredients contact an aqueous liquidenvironment the bioactive materials are gradually released into theenvironment. Accordingly, the compositions of this invention are usefulfor releasing such ecological agents into bodies of water or into a landenvironment where they may release their active agents by contact withrain or standing water, so as to maintain an effective concentration ofthe agent in the environment for a relatively long period of time.

It is preferred to use the erodible matrix of this invention as acarrier for sustained release pharmaceuticals administered orally toindividuals in need of a relatively constant concentration ofmedication. The drugs may be locally or systemically acting drugs, andmay be selected from among any group wherein a steady concentration ofthe drug in the organism is desired. Accordingly, the drug may beselected from among analgesic, anorexic, antiarthritic, antibacterial,antibiotic, anticonvulsant, anti-depressant, antidiabetic, anti-fungal,antihistaminic, anti-hypertensive, anti-inflammatory, anti-neoplastic,antiparkinsonism, antipyretic, anticholinergic, anti-inflammatory,anesthetic, antimicrobial, antiviral, anti-ulcer, bronchodilator,cardiovascular, contraceptive, central nervous system affecting,inotropic, vasodilator, vasoconstrictor, decongestant, diuretic,hypoglycemic, hormone, hypnotic, hematinic, electrolyte supplement,germicidal, muscle relaxant, parasympathetolytic, parasympathetomimetic,tranquilizer, ophthalmic, psychostimulant, vitamin, and the like drugs.The drugs can be administered in the form of the parent compound as wellas in the form of pharmaceutically acceptable salts, and precursors.

Preferred drugs for use in the dosage forms prepared according to theinvention include clonidine, theophylline, dipyridamole,hydrochlorothiazide, scopolamine, indomethacin, furosemide, potassiumchloride and the like.

The drug to be released from the dosage form of the invention may beincorporated into the erodible matrix simply by dissolving it in themolten matrix or mixing it therewith.

The proportions of drug and erodible matrix in the dosage forms of thisinvention may vary within wide limits. Because some drugs are effectivein very small doses and others require relatively large doses foreffect, the proportions will vary depending on the amount of drug whichmust be incorporated into the unit dosage form. Accordingly, the drugmay be constitute in an effective amount up to about 70 % by weight ofthe composition. More preferably the drug will constitute from about 0.1% to about 50 % by weight of the composition, with the balance being theerodible matrix.

The unit dosage forms of the invention can be prepared by conventionalprocedures such as compression molding, tableting, extrusion, andinjection molding. It is preferred that the dosage forms of theinvention be non-porous in order that the erosion will proceed from thesurface of the dosage form. Such non-porous dosage forms are bestprepared by solidification of a molten form of the compositioncontaining all ingredients of the composition, and injection molding isespecially useful for that purpose. Indeed, the dosage forms of theinvention are especially adapted to production by injection moldingbecause the erodible matrix composition of the invention has arelatively low melting temperature, and hence the injection molding canbe carried out at a temperature which is not detrimental to the drugcontained in the dosage form.

The preferred dosage forms of the invention have a cylindrical shapewith a diameter of about 3 mm to about 8 mm, and preferably about 5 mm.The length of the cylindrical dosage form is typically about 5 mm toabout 20 mm, and is preferably about 10 mm. The preferred dosage formsmay be coated on their peripheral cylindrical surfaces with aliquid-impervious non-self-supporting coating as discussed above.

The sustained release compositions of this invention are prepared by thefollowing general procedure.

A premeasured amount of a polyethylene glycol is melted in a vessel, e.g., a kettle provided with a steam jacket or a heating mantle andequipped with a stirring mechanism. A temperature of about 85° C. issufficient to melt any of the polyethylene glycols. The premeasuredamount of the insoluble amphiphile is then added either as a moltenliquid or as a solid. It is preferred to melt the insoluble amphiphileand add it slowly to the stirred molten PEG. The long chain fattyamphiphiles useful in the compositions of this invention are generallymolten at the temperature of the molten PEG and can be readily mixedwith the PEG. The bioactive agent, drug or the like is then added anddissolved in the molten mixture. Other ingredients, such asdisintegrants (e. g., starch), molding adjuvants (e. g., polyethyleneoxide), and the like are then added and the mixture is thoroughlyblended. Dosage forms may then be formed directly from the moltenmixture by the procedures outlined above.

The invention will now be further elucidated by the following exampleswhich are included by way of illustration only and are not intended tobe limiting. In the examples all percentages and parts are weight unlessotherwise specified.

EXAMPLE 1

This example illustrates the preparation of dosage forms of theinvention containing polyethylene glycols of various molecular weights.

A series of compositions were prepared having the followingcompositions:

    ______________________________________                                        A.           PEG-1000   37.5%                                                              Myristic acid                                                                            15%                                                                Starch     22.5%                                                              Indomethacin                                                                             25%                                                   B.           PEG-4000   37.5%                                                              Myristic acid                                                                            15%                                                                Starch     22.5%                                                              Indomethacin                                                                             25%                                                   C.           PEG-8000   37.5%                                                              Myristic acid                                                                            15%                                                                Starch     22.5%                                                              Indomethacin                                                                             25%                                                   D.           PEG-20,000 37.5%                                                              Myristic acid                                                                            15%                                                                Starch     22.5%                                                              Indomethacin                                                                             25%                                                   ______________________________________                                    

Cylindrical dosage forms were molded from the compositions A-D bypouring the molten compositions into open-ended plastic molds made ofpolyethylene having a diameter of about 6 mm and allowing the melt tocool to room temperature. The solidified composition was then extrudedfrom the molds and cut into lengths to prepare cylindrical dosage forms.In this way dosage forms having a diameter of about 6 mm and a length ofabout 14 mm and weighing about 0.44 g each were prepared.

The sustained release properties of the dosage forms were then tested bythe following procedure:

Simulated intestinal fluid (SIF) was prepared by the followingprocedure:

(1) 6.8 g of monobasic potassium phosphate were dissolved in 250 ml ofwater.

(2) 190 ml of 0.2 N NaOH was added with stirring.

(3) 400 ml of water and 10 ml of pancreatin were added.

(4) The pH of the solution was adjusted with 0.2 N NaOH to 7.5 ±0.1.

(5) The solution was diluted with water to 1000 ml.

Each of the cylindrical dosage forms was placed in 80 ml of SIF at 37 °C. and subjected to gentle agitation. The amount of drug released wasmonitored by measuring the optical density of the aqueous medium at anabsorption peak of indomethacin at intervals using an ultravioletspectrophotometer. Each of the dosage forms was found to release thedrug gradually over a period of several hours.

Cylindrical dosage forms of the same size and shape as above wereprepared from each of the compositions A-D, but these cylinders werecoated on their cylindrical surfaces with myristic acid by dipping thecylinders in molten myristic acid, withdrawing the cylinders andallowing the myristic acid coating to cool and harden, and then scrapingthe coating from the ends of the cylinders. These dosage forms weretested in SIF by the same procedure as the uncoated dosage forms. Theyalso were found to release the drug over a period of several hours withthe drug release occurring at an approximately constant rate.

EXAMPLE 2

This example illustrates variation of the fatty acid erosion ratemodifier.

Several dosage forms were prepared by the procedure of Example 1 havingthe following compositions:

    ______________________________________                                        A.           PEG-8000   37.5%                                                              Myristic acid                                                                            15%                                                                Starch     22.5%                                                              Indomethacin                                                                             25%                                                   B.           PEG-8000   37.5%                                                              Palmitic acid                                                                            15%                                                                Starch     22.5%                                                              Indomethacin                                                                             25%                                                   C.           PEG-8000   37.5%                                                              Stearic acid                                                                             15%                                                                Starch     22.5%                                                              Indomethacin                                                                             25%                                                   ______________________________________                                    

The dosage forms were tested by the procedure of Example 1 and werefound to release the drug over a period of several hours at a relativelyconstant rate.

EXAMPLE 3

This example illustrates another composition of the inventionincorporating additional ingredients.

A sustained release composition was prepared by the general proceduredisclosed above having the following composition:

    ______________________________________                                        PEG-8000           27%                                                        Palmitic acid      13%                                                        PEG 400 monostearate                                                                             10%                                                        PEO (MW 5 × 10.sup.6)                                                                        0.1%                                                     Cornstarch           49.8%                                                    Clonidine HCl        0.1%                                                     ______________________________________                                    

The molten mixture was poured onto a surface and allowed to cool andsolidify. The solid material was then granulated and fed into aninjection molding machine to form dosage forms according to theinvention.

EXAMPLE 4

This example illustrates the preparation of dosage forms whose releaserate varies with pH.

Uncoated dosage forms of the following composition were prepared by theprocedure of Example 1 above:

    ______________________________________                                        PEG-8000          2.8 g                                                       Myristic acid     1.1 g                                                       Starch            1.6 g                                                       Sodium bicarbonate                                                                              0.5 g                                                       Indomethacin      2.0 g                                                       ______________________________________                                    

Simulated gastric fluid was prepared by dissolving 2 g of sodiumchloride and 3.2 g of pepsin in 7 ml of hydrochloric acid, then dilutingthe solution to a volume of 1000 ml. The pH of the SGF was about 1.2.

The dosage forms were tested by the procedure of Example 1 in SIF andSGF. It was found that the rate of drug release was substantially fasterin SIF.

EXAMPLE 5

This example illustrates preparation of PEG esters.

PEG-8000 was melted in a vessel equipped with a stirrer and heated to100° C. An amount of myristyl chloride equivalent to one half of theterminal hydroxyl groups of the PEG was melted and added dropwise to themolten PEG with continuous stirring. Chloroform was added to the mixtureand the solution was filtered through filter paper (Whatman No. 4) andallowed to stand overnight to evaporate the solvent. The remainingsolvent was evaporated the next day by heating at 60° C. The material soobtained was a hard waxy solid having a melting point of about 60° C.

EXAMPLE 6

This example illustrates the preparation of dosage forms of theinvention using various drugs.

Sustained release compositions were prepared by the general proceduredisclosed above having the following compositions:

    ______________________________________                                        A.        PEG (MW 3,350)  35%                                                           Stearyl alcohol 15%                                                           Theophylline    50%                                                 B.        PEG 8000        30%                                                           Myristic acid   20%                                                           PEG 400 monostearate                                                                          10%                                                           PEO (MW 5 × 10.sup.6)                                                                     0.1%                                                        Corn starch       24.9%                                                       Dipyridamole    15%                                                 C.        PEG-8000        2.8      g                                                    Myristic acid   1.2      g                                                    Starch          1.8      g                                                    Hydrochlorothiazide                                                                           50       mg                                         D.        PEG-8000        1.5      g                                                    Myristic acid   0.6      g                                                    Starch          0.9      g                                                    Furosemide      1.0      g                                          E.        PEG-8000         5%                                                           Myristic acid   10%                                                           Starch          15%                                                           Flubiprofen     70%                                                 F.        PEG-1000        0.7      g                                                    PEG-8000        0.7      g                                                    PEG-20000       0.7      g                                                    Myristic acid   1.0      g                                                    Palmitic acid   1.0      g                                                    Stearic acid    1.0      g                                                    Starch          0.9      g                                                    KCl             6.0      g                                          G.        PEG-8000        50%                                                           Glyceryl monostearate                                                                          5%                                                           Starch          20%                                                           Dipyridamole    25%                                                 ______________________________________                                    

EXAMPLE 7

This example illustrates a dosage form of this invention incorporating apesticide.

A composition of the invention was prepared by the procedure of Example1 having the following composition:

    ______________________________________                                               PEG-8000 37.5%                                                                Myristic acid                                                                          15.0%                                                                Starch   22.5%                                                                Carbofuran                                                                             25.0%                                                         ______________________________________                                    

Cylindrical dosage forms (uncoated) were prepared by the procedure ofExample 1. These dosage forms were found to erode over a period of aboutone day in an aqueous environment.

EXAMPLE 8

This example illustrates the preparation of a coated dosage form of theinvention.

A composition was prepared by the procedure of Example 1 having thefollowing composition:

    ______________________________________                                        PEG-3350          27%                                                         Myristic acid     13%                                                         PEG-400 distearate                                                                               2%                                                         Potato starch     13%                                                         Quinidine.2 H.sub.2 SO.sub.4                                                                    45%                                                         ______________________________________                                    

After mixing the molten composition was poured onto a surface andallowed to cool and harden. The hardened composition was then granulatedand introduced into an extrusion apparatus. A cylindrical stream wasextruded from the apparatus and coextruded therewith, so as to form acontinuous coating over the extruded cylinder, was a liquid imperviouscoating having the following composition:

    ______________________________________                                        Cetyl alcohol    99%                                                          Diethyl phthalate                                                                               1%                                                          ______________________________________                                    

The extruded cylinder was then cut into dosage forms having a length ofabout 10 mm and dosage forms were tested as in Example 1 and found torelease the drug over a period of time.

EXAMPLE 9

This example illustrates controlled release compositions of thisinvention having a relatively rapid release rate for the bioactivecompound contained therein.

Dosage form were prepared by the procedure of Example 1 having thefollowing compositions:

    ______________________________________                                        A.      PEG 3350           45%                                                        Stearic acid        5%                                                        Starch             25%                                                        Pseudoephedrine hydrochloride                                                                    25%                                                B.      PEG 3350           49%                                                        Stearic acid        1%                                                        Starch             25%                                                        Pseudoephedrine hydrochloride                                                                    25%                                                C.      PEG 3350           50%                                                        Starch             25%                                                        Pseudoephedrine hydrochloride                                                                    25%                                                D.      PEG 3350           45%                                                        Palmitic acid       5%                                                        Starch             25%                                                        Pseudoephedrine hydrochloride                                                                    25%                                                E.      PEG 3350             49.5%                                                    Palmitic acid        0.5%                                                     Starch             25%                                                        Pseudoephedrine hydrochloride                                                                    25%                                                F.      PEG 3350           45%                                                        Stearyl alcohol     5%                                                        Starch             25%                                                        Pseudoephedrine hydrochloride                                                                    25%                                                G.      PEG 3350           48%                                                        Stearyl alcohol     2%                                                        Starch             25%                                                        Pseudoephedrine hydrochloride                                                                    25%                                                H.      PEG 3350           48%                                                        Stearyl alcohol     2%                                                        Starch             25%                                                        Theophylline       25%                                                I.      PEG 3350           50%                                                        Starch             25%                                                        Theophylline       25%                                                ______________________________________                                    

The dosage forms were tested by the procedure of Example 1 and werefound to release the drug over a period of one-half hour to about fourhours. The results for preparations A-C are shown in the drawing, wherethe drug release rates curves are identified by the letter correspondingto the formula in this example. In every case, lower concentrations ofamphiphile gave a more rapid release of drug in comparison to similarformulations having a higher concentration of the same amphiphile.

The invention having now been fully described, it should be understoodthat it may be embodied in other specific forms or variations withoutdeparting from its spirit or essential characteristics. Accordingly, theembodiments described above are to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A composition erodible by an aqueous liquidcomprising5 to 99.5 % by weight of a polyethylene glycol having amolecular weight of from about 1000 to about 20,000, and 95 to 0.5 % byweight of an erosion rate modifier which is an amphiphilic compoundinsoluble in said aqueous liquid, the molecular structure of saidamphiphilic compound having a lipophilic portion and a hydrophilicportion.
 2. The composition of claim 1 wherein said polyethylene glycolhas a molecular weight of about
 8000. 3. The composition of claim 1wherein said erosion rate modifier is a C₁₂ -C₂₀ fatty acid.
 4. Thecomposition of claim 3 wherein said fatty acid is selected from thegroup consisting of myristic acid and stearic acid.
 5. The compositionof claim 1 additionally comprising a substance which increases thecompatibility of the polyethylene glycol and the erosion rate modifier.6. The composition of claim 5 wherein said substance is a polyethyleneglycol having a molecular weight from about 200 to about 10000 andhaving at least one of its terminal OH groups esterified with a C₁₂ -C₂₀fatty acid.
 7. The composition of claim 6 wherein said polyethyleneglycol is polyethylene glycol
 400. 8. The composition of claim 7 whereinsaid substance is polyethylene glycol 400 having at least one of itsterminal OH groups esterified with stearic acid.
 9. The composition ofclaim 1 additionally comprising a disintegrant.
 10. The composition ofclaim 9 wherein said disintegrant is starch.
 11. The composition ofclaim 1 additionally comprising a molding adjuvant.
 12. The compositionof claim 11 wherein said molding adjuvant is polyethylene oxide having amolecular weight of 100,000 to 5,000,000.
 13. A sustained releasecomposition for releasing a biologically active compound into itssurrounding environment comprising said biologically active compounddispersed in a matrix which, when contacted with an aqueous liquid,erodes progressively, said matrix comprising a mixture of5 to 99.5 % byweight of a polyethylene glycol having a molecular weight of from about1000 to about 20,000, and 95to 0.5 % by weight of an erosion ratemodifier which is an amphiphilic compound insoluble in said aqueousliquid, the molecular structure of said amphiphilic compound having alipophilic portion and a hydrophilic portion.
 14. The composition ofclaim 13 wherein said polyethylene glycol has a molecular weight ofabout
 8000. 15. The composition of claim 13 wherein said erosion ratemodifier is a C₁₂ -C₂₀ fatty acid.
 16. The composition of claim 15wherein said fatty acid is selected from the group consisting ofmyristic acid and stearic acid.
 17. The composition of claim 13additionally comprising a substance which increases the compatibility ofthe polyethylene glycol and the erosion rate modifier.
 18. Thecomposition of claim 17 wherein said substance is a polyethylene glycolhaving a molecular weight from about 200 to about 10000 and having atleast one of its terminal OH groups esterified with a C₁₂ -C₂₀ fattyacid.
 19. The composition of claim 18 wherein said polyethylene glycolis polyethylene glycol
 400. 20. The composition of claim 19 wherein saidsubstance is polyethylene glycol 400 having at least one of its terminalOH groups esterified with stearic acid.
 21. The composition of claim 13additionally comprising a disintegrant.
 22. The composition of claim 21wherein said disintegrant is starch.
 23. The composition of claim 13additionally comprising a molding adjuvant.
 24. The composition of claim23 wherein said molding adjuvant is polyethylene oxide having amolecular weight of 100,000 to 5,000,000.
 25. A sustained releasecomposition for releasing a biologically active compound into itssurrounding environment comprising a pharmaceutically active compound ornon-toxic pharmaceutically acceptable salt of said pharmaceuticallyactive compound dispersed in a matrix which, when contacted with anaqueous liquid, erodes progressively, said matrix comprising a mixtureof5to 99.5 % by weight of a polyethylene glycol having a molecularweight of from about 1000 to about 20,000, and 95 to 0.5 % by weight ofan erosion rate modifier which is an amphiphilic compound insoluble insaid aqueous liquid, the molecular structure of said amphiphiliccompound having a lipophilic portion and a hydrophilic portion.
 26. Thecomposition of claim 25 wherein said compound is clonidine.
 27. Thecomposition of claim 25 wherein said compound is dipyridamole.
 28. Thecomposition of claim 25 wherein said compound is hydrochlorothiazide.29. The composition of claim 25 wherein said compound is furosemide. 30.The composition of claim 25 wherein said compound is indomethacin. 31.The composition of claim 25 wherein said compound is scopolamine. 32.The composition of claim 25 wherein said compound is a bronchodilator.33. The composition of claim 32 wherein said bronchodilator istheophylline.
 34. The composition of claim 25 wherein said compound isquinidine.
 35. The composition of claim 25 wherein said compound isnaproxen.
 36. The composition of claim 25 wherein said compound ispropranolol.
 37. The composition of claim 25 wherein said compound is asalicylate.
 38. The composition of claim 37 wherein said salicylate isaspirin.
 39. The composition of claim 25 wherein said compound isnitroglycerin.
 40. The composition of claim 25 wherein said compound isisosorbide dinitrate.
 41. A sustained release composition for releasingan ecologically active compound into its surrounding environmentcomprising said ecologically active compound dispersed in a matrixwhich, when contacted with an aqueous liquid, erodes progressively, saidmatrix comprising a mixture of5to 99.5 % by weight of a polyethyleneglycol having a molecular weight of from about 1000 to about 20,000, and95 to 0.5 % by weight of an erosion rate modifier which is anamphiphilic compound insoluble in said aqueous liquid, the molecularstructure of said amphiphilic compound having a lipophilic portion and ahydrophilic portion.
 42. The composition of claim 41 wherein saidecologically active compound is a fertilizer.
 43. The composition ofclaim 41 wherein said ecologically active compound is a pesticide. 44.The composition of claim 41 wherein said ecologically active compound isan insecticide.
 45. The composition of claim 41 wherein saidecologically active compound is an herbicide.
 46. A sustained releasedosage form for releasing a biologically active compound into an aqueousliquid environment comprising a non-porous solid erodible matrix havingdispersed therein a biologically active compound, said matrix comprisinga mixture of5 to 99.5 % by weight of a polyethylene glycol having amolecular weight of from about 1000 to about 20,000, and 95to 0.5 % byweight of an erosion rate modifier which is an amphiphilic compoundinsoluble in said aqueous liquid, the molecular structure of saidamphiphilic compound having a lipophilic portion and a hydrophilicportion.
 47. The dosage form of claim 46 wherein said polyethyleneglycol has a molecular weight of about
 8000. 48. The dosage form ofclaim 46 wherein said erosion rate modifier is a C₁₂ -C₂₀ fatty acid.49. The dosage form of claim 48 wherein said fatty acid is selected fromthe group consisting of myristic acid and stearic acid.
 50. The dosageform of claim 46 additionally comprising a substance which increases thecompatibility of the polyethylene glycol and the erosion rate modifier.51. The dosage form of claim 50 wherein said substance is a polyethyleneglycol having a molecular weight from about 200 to about 10000 andhaving at least one of its terminal OH groups esterified with a C₁₂ -C₂₀fatty acid.
 52. The dosage form of claim 51 wherein said polyethyleneglycol is polyethylene glycol
 400. 53. The dosage form of claim 52wherein said substance is polyethylene glycol 400 having at least one ofits terminal OH groups esterified with stearic acid.
 54. The dosage formof claim 46 additionally comprising a disintegrant.
 55. The dosage formof claim 54 wherein said disintegrant is starch.
 56. The dosage form ofclaim 46 additionally comprising a molding adjuvant.
 57. The dosage formof claim 56 wherein said molding adjuvant is polyethylene oxide having amolecular weight of 100,000 to 5,000,000.
 58. The dosage form of claim46 wherein said biologically active compound is a pharmaceuticallyactive compound or non-toxic pharmaceutically acceptable salt of saidcompound and said dosage form contains an effective amount of saidcompound or said salt.
 59. The dosage form of claim 58 wherein saidcompound is clonidine.
 60. The dosage form of claim 58 wherein saidcompound is dipyridamole.
 61. The dosage form of claim 58 wherein saidcompound is hydrochlorothiazide.
 62. The dosage form of claim 58 whereinsaid compound is furosemide.
 63. The dosage form of claim 58 whereinsaid compound is indomethacin.
 64. The dosage form of claim 58 whereinsaid compound is scopolamine.
 65. The dosage form of claim 58 whereinsaid compound is a bronchodilator.
 66. The dosage form of claim 65wherein said bronchodilator is theophylline.
 67. The dosage form ofclaim 58 wherein said compound is quinidine.
 68. The dosage form ofclaim 58 wherein said compound is naproxen.
 69. The dosage form of claim58 wherein said compound is propranolol.
 70. The dosage form of claim 58wherein said compound is a salicylate.
 71. The composition of claim 70wherein said salicylate is aspirin.
 72. The dosage form of claim 58wherein said compound is nitroglycerin.
 73. The dosage form of claim 58wherein said compound is isosorbide dinitrate.
 74. The dosage form ofclaim 46 wherein said dosage form has the shape of a cylinder.
 75. Thedosage form of claim 74 wherein said cylinder has a diameter from about3 mm to about 8 mm.
 76. The dosage form of claim 75 wherein saidcylinder has a diameter of about 6 mm.
 77. The dosage form of claim 74wherein said cylinder has a length from about 5 mm to about 20 mm. 78.The dosage form of claim 77 wherein said cylinder has a length of about10 mm.
 79. The dosage form of claim 74 additionally comprising at leasta partial coating of a liquid impermeable non-self-supporting coating.80. The dosage form of claim 79 wherein said coating comprises a solidC₁₂ -C₂₀ fatty acid.
 81. The dosage form of claim 80 wherein saidcoating comprises myristic acid.
 82. The dosage form of claim 80 whereinsaid coating comprises palmitic acid.
 83. The dosage form of claim 79wherein said dosage form has a cylindrical shape and is coated on itsperipheral cylindrical surface with a liquid-imperviousnon-self-supporting coating.